Tous les cancers du rein ne sont pas pareils.

An urgent question for cancer scientists is why immunotherapy achieves dramatic results in some cases but doesn't help most patients. Now, two research groups from Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.

The scientists say the findings reveal potential new drug targets and might aid efforts to extend the benefits of immunotherapy treatment to more patients and additional types of cancer.

The discoveries are detailed in two articles published by the journal Science.

One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, is from scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, led by Eliezer Van Allen, MD, of Dana-Farber and the Broad, and Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The second report, identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, MD, PhD, director of Dana-Farber's Center for Cancer Immunotherapy Research, and Shirley Liu, PhD, of Dana-Farber.

The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodeling complex, is known as SWI/SNF; its components are encoded by different genes, among them ARID2, PBRM1, and BRD7. SWI/SNF's job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.

Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell cancer (ccRCC) gain clinical benefit -- sometimes durable -- from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don't.

The scientists' curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer, and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive "neoantigens" that help the patient's immune system recognize and attack tumors, and make the cancer cells' "microenvironment" hospitable to tumor-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.

To search for other characteristics of ccRCC tumors that influences immunotherapy response or resistance, the researchers used whole-exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analyzed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.

When the data was sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumors lacked a functioning PRBM1 gene. (About 41 percent of patients with ccRCC kidney cancer have a non-functioning PBRM1 gene.) That gene encodes a protein called BAF 180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodeling complex.

Loss of the PBRM1 gene function caused the cancer cells to have increased expression of other genes, including gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.

While the finding does not directly lead to a test for immunotherapy response yet, Choueiri said, "We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations."

In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 technique to sift the genomes of melanoma cells for changes that made tumors resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells. The search turned up about 100 genes which appeared to govern melanoma cells' resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodeling complex -- the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells -- as being involved in resistance to immune T cells.

When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon-gamma produced by T cells, and in response produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex -- ARID2 and BRD7 -- are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors note, "represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack." Finding ways to alter those target molecules, they add, "will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy."

Solving that puzzle could have implications for the diagnosis and treatment if kidney cancer, which has 35 per cent mortality rate and is becoming more common. Despite advances in early detection and treatment, the mortality rate hasn't changed in decades.

For the first time, researchers at St. Michael's Hospital have looked at multiple different levels of changes at the same time. Dr. George Yousef, a laboratory pathologist, said researchers have looked at three different ways cancer cells can grow and survive:

the tumour can amplify (or replicate) its chromosomes, the packages of DNA and proteins found in cells the tumour can alter a process that controls the on-off switch for genes needed for cell growth and differentiation, known as methylation or the tumour can drive gene activation through another gene

Dr. Yousef said they found that looking at all these changes in the same setting simultaneously can provide a much better understanding of tumour behaviour and how the apparently different changes can produce the same results.

His research appears in the journal Cancer Research, one of the leading journals of in the field of cancer.

Using a high resolution microarray there were also able to identify very specific regions of the chromosomes where genetic alterations happen in kidney cancer to a much higher resolution than before. Combining information from chromosomal changes, methylation and gene expression provided a much clearer understanding of the mechanism of kidney cancer development.

"Now we look at the mechanism rather than the individual change," Dr. Yousef said. "Regardless of the apparent differences of the tumour, the outcome will be the same. Eventually, we may be able to target treatment based on the 'mechanism' that is affected rather than the individual genes that are changed."

A study of nearly 1,500 patients treated for kidney cancer at UCLA in the last 15 years shows that an aggressive, tailored treatment approach results in better survival rates and uncovered subsets of kidney cancer that behave differently and need to be treated accordingly.

The one-size-fits-all approach traditionally used in kidney cancer treatment should be changed based on the results of the study, the longest to date to analyze kidney cancer patients and their outcomes, said Dr. Arie Belldegrun, senior author of the study, a professor of urology and a researcher at UCLA's Jonsson Comprehensive Cancer Center.

"This is the most important work that we've done out of the kidney cancer program at UCLA," Belldegrun said. "We outline the foundation for personalized kidney cancer therapy. We have shown that not all kidney cancer patients are the same, not all localized kidney cancers are the same and not all metastatic kidney cancers are the same."

The study appears in the Nov. 1, 2008 issue of Cancer, the peer-reviewed journal of the American Cancer Society.The study found that patients with localized kidney cancer, cancer that has not spread to other organs, could have either low, intermediate or high risk cancers based on the chance for recurrence. Patients with cancers that have already spread also fell into similarly different subsets. Some have better outcomes while others may have very aggressive cancers that may not warrant treatment.

"We showed for the first time, using an integrated staging system developed at UCLA, that we can identify which patients with localized disease fall into the low, intermediate and high risk subsets and which patients with metastasized cancers are either low, intermediate or high risk patients," Belldegrun said. "Now we can make treatment decisions based on that."

If a patient with localized cancer is identified as low risk, his five-year survival rate is expected to be 97 percent, while his 10-year survival rate is 92 percent. An intermediate risk patient with localized disease would have a five-year survival rate of 81 percent and a 10-year survival rate of 61 percent. A high risk patient has a five-year survival rate of 62 percent, with a 10-year survival of 41 percent.

"All of these patients with cancers that have not spread present to their doctors with presumably localized disease and in the past they may have been treated the same way," Belldegrun said. "They need to be treated individually according to their risk levels."

"Tous ces patients auraient traités de façon semblable..."

The study showed that a patient with low-risk, localized kidney cancer could be treated only with surgery and expect an excellent outcome. Such a move would spare the patient from having to undergo radiation or immunotherapy, which result in harsh side effects. However, for a patient with high-risk, localized kidney cancer, surgery would not be enough. Additional therapy such as targeted treatments or immunotherapy should be considered in order to give the patient the best possible outcome.

In metastatic patients, someone with low-risk cancer should get very aggressive treatment, Belldegrun said, because there's a good chance the therapy will help the patient. Those with high-risk, metastatic disease won't get much, if any, benefit from treatment and may want to forego surgery and the toxic therapies.

"Our paper identifies, very precisely, which patients should get which therapies," Belldegrun said.The study represents 15 years of experience in UCLA's leading-edge kidney cancer program, an interdisciplinary approach to treating cancer that brings together medical oncologists, urologists, surgeons, clinical trials experts and scientists under one roof, a concept that was first conceptualized at UCLA. The study analyzed the first 1,492 patients treated in the program and "demonstrated that outstanding results can be achieved using this approach," Belldegrun said.

About 25 percent of the patients with metastatic kidney cancer achieved long-term responses – five to 15 year survivals – from their therapy, Belldegrun said. Less than 5 percent of metastatic kidney cancer patient typically achieve long term survivals or a cure when treated with conventional treatments.

"This is by far the best survival data in such a difficult group of patients," Belldegrun said. "This can be achieved today only in kidney cancer centers of excellence like we are operating at UCLA, where we have all the expertise at hand, the best scientists, clinicians and surgeons working together."

The results of the study come as new targeted therapies are being introduced specifically for kidney cancer. The U.S. Food & Drug Administration has recently approved three such drugs. Belldegrun said the survival rates detailed in their paper should be used as a benchmark to which these new therapies should be compared.

"While the field of kidney cancer is undergoing dramatic changes it is as yet still unclear how these changes are affecting patient outcome," the study states. "A critical assessment of the potential improvement in the new treatment era necessitates a comparison to a known benchmark. We present long-term, single institution data to provide a thorough understanding of the results that have been achieved until now using a consistent, aggressive approach for localized and metastatic disease. For future patient care, it will be important to select patients that will do best using existing therapies, and those who should be treated using the newly approved treatments."